Antiarthritic profile of BF-389--a novel anti-inflammatory agent with low ulcerogenic liability.

Abstract

BF-389, dihydro-4-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-methyl-2H-1,2- oxazin-3(4H)-one, is a potent, orally active, antiarthritic and analgesic agent with low ulcerogenic potential. A comparison of the activity profiles of BF-389 and naproxen showed similarities in: (1) suppression of developing and chronic adjuvant arthritis (AA); (2) maximal inhibitory response, as shown by the E(max) values in the developing and established AA models; (3) inhibition of bone degenerative changes associated with chronic adjuvant arthritis; and (4) analgesic activity in the acetic acid and phenylquinone writhing assays. Though BF-389 has been shown to be a potent inhibitor of cyclooxygenase, IC50 = 0.84 +/- 0.25 microM against the production of PGE2 in vitro, there is a great difference from most cyclooxygenase inhibitors; it also inhibits the 5-lipoxygenase enzyme. For BF-389, the IC50 for in vitro LTB4 formation was found to be 3.65 +/- 1.19 microM. The ulcerogenic potential of BF-389 was compared to that of naproxen using a five-day in vivo ulcerogenic rat assay. The UD50 for naproxen was found to be approximately 30 mg/kg/day, p.o. Based upon efficacy in the DEV AA and EST AA models, UD50/ED50 values for naproxen were estimated to be 0.7 and 1.9, respectively. For BF-389 the UD50 was shown to be 520 (389-695) mg/kg/day, p.o., and the corresponding UD50/ED50 values were calculated to be 84 and 28, respectively, thus demonstrating the wide margin of safety between efficacy and ulcerogenicity in rats.

• Authors: S Wong, S J Lee, M R Frierson 3rd, J Proch, T A Miskowski, B S Rigby, S J Schmolka, R W Naismith, D C Kreutzer, R Lindquist
• Journal: Agents and actions (Agents Actions) Vol. 37 Issue 1-2 Pg. 90-8 (Sep 1992) ISSN: 0065-4299 [Print] Switzerland
• PMID: 1456184 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Oxazines
• Phenols
• Biofor 389
• Arachidonic Acid

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Arachidonic Acid (metabolism)
• Arthritis, Experimental (drug therapy)
• Disease Models, Animal
• Edema (drug therapy)
• Female
• Male
• Mice
• Oxazines (pharmacology)
• Pain Measurement
• Peptic Ulcer (chemically induced)
• Phenols (pharmacology)
• Rats
• Rats, Inbred Lew
• Rats, Sprague-Dawley